PROJECT SUMMARY The incidence and mortality rates of hepatocellular carcinoma (HCC) is rapidly increasing in the United States, with the highest rates found among Hispanics in South Texas. We reported that the prevalence of cirrhosis, the main risk factor for HCC, in Hispanics in South Texas is 4-times higher than the national average and identified central obesity and diabetes as the main risk factors. The role of obesity and diabetes in liver cirrhosis in Hispanics in South Texas likely contributes to the high prevalence of HCC associated with non-alcoholic steatohepatitis (NASH) in this population. The burden of NASH in this population is more substantial than predicted, affecting close to 20% of the population including children. To address the magnitude of this growing health-disparity problem, it is critically important to identify those at high risk for HCC who would benefit from surveillance and prevention strategies. HCC is a genetically heterogeneous disease and specific somatic mutations profiles are associated with different etiologies. Hispanic ethnicity and NASH etiology are critically underrepresented in HCC genomic studies. Therefore, there is a need for molecular characterization of NASH- associated HCC in Hispanics, to identify opportunities for biomarker and targeted therapy development. Because HCC somatic mutations have been detected in circulating cell free DNA (cfDNA) in patients with HCC but also in patients with pre-HCC conditions such as cirrhosis, one such opportunity is the detection in cfDNA, of selected somatic mutations for HCC risk assessment and early detection. We hypothesize that the tumor genomic landscape of HCC in Hispanics in South Texas is representative of the underlying liver diseases and environmental factors affecting this population and that selected HCC somatic mutations can be detected in plasma cfDNA at early HCC stage or prior to diagnosis and could therefore have utility in HCC risk assessment and early detection. In Aim 1, we will determine the tumor genomic landscape of NASH-associated HCC in Hispanics in South Texas and identify (if any) unique features of HCC in this population. In Aim 2, we will custom-design a targeted sequencing panel to detect with high sensitivity the most common HCC somatic mutations identified in Aim 1, in plasma cfDNA of patients with NASH-associated HCC. In Aim 3, we will determine the utility of the mutation-based model identified in Aim 2 and applied to cfDNA, in HCC risk prediction in Hispanics in South Texas using two large population-based Hispanic cohorts. This project is supported by extensive preliminary data, unique resources and a strong multidisciplinary research team. It will represent the largest genomic study of HCC associated with NASH, diabetes and obesity in an underserved population particularly affected by these chronic diseases. The project impact and translational goals are: 1) to serve the Hispanic population in South Texas, a population with health and healthcare disparities and high rates of diabetes, obesity, NASH and HCC; and 2) to develop new tests to identify, in this population, subjects at high risk for HCC and institute effective surveillance and prevention strategies, improving survival.